Both (R)- and (S)-3-aminopiperidine are valuable building blocks for the preparation of bioactive compounds, such as antagonistic ligands of receptors in the central nervous system. (R)-3-aminopiperidine is also known to be a key intermediate for the synthesis of dipeptidyl peptidase-4 inhibitors, such as alogliptin and linagliptin, and a protein kinase inhibitor.
Several approaches for the enantioselective preparation of (R)-3-aminopiperidine have been described in the art that rely on the cyclization of α-amino acids or their derivatives, such as D-ornithine and derivatized D-glutamic acid, or on the hydrogenation of usually derivatized 3-aminopyridine followed by enantiomeric separation. These approaches typically require expensive starting materials, a large number of synthesis steps, or expensive hydrogenation catalysts including platinum group metals, and are therefore not suitable for industrial scale syntheses.
Alternatively, 3-aminopiperidine derivatives have been prepared in the prior art, either in the form of the R-enantiomer or in the form of the racemate, via a Curtius or Hofmann rearrangement of N-protected nipecotic acid (piperidine-3-carboxylic acid) derivatives. Particular examples of this approach are the following:
US 2001/0056090 describes the synthesis of (R)-3-benzyloxycarbonylamino-1-tert-butyloxycarbonyl-piperidine by reacting N-tert-butyloxycarbonyl-protected (R)-nipecotic acid with isobutylchoroformate/triethylamine and then sodium azide. The obtained acyl azide is then subjected to a Curtius rearrangement yielding the corresponding isocyanate which is heated with benzyl alcohol to give the title compound.
Jean et al., Tetrahedron Letters 2001, 42, 5645-5649, disclose Curtius rearrangement of N-benzyl protected nipecotic acid hydrazide in the presence of sodium nitrite yielding 1-benzyl-3-aminopiperidine.
US 2010/0105917 discloses Hofmann rearrangement of (R)-nipecotic acid amide, which is N-protected with a tert-butyloxycarbonyl group or an optionally substituted benzoyl group, to the correspondingly N-protected (R)-3-aminopiperidine.
The additional steps for introducing and removing an N-protecting group that are required in the aforementioned 3-aminopiperidine synthetic routes are particularly disadvantageous for the preparation of (R)-3-aminopiperidine on an industrial scale.
Furthermore, JP 2011/012032 discloses methods for the enantiomeric resolution of racemic or insufficiently enantiomerically enriched 3-aminopiperidine, which methods are based on the crystallization of the diastereomeric acid addition salts of one of the enantiomers. According to this document (R)-3-aminopiperidine can be obtained from the racemate by crystallizing it as its acid addition salt that is formed in the presence of 2 equivalents of (R)-2-methoxy-2-phenylacetic acid or 2 equivalents of N-(para-toluenesulfonyl)-L-phenylalanine. Unfortunately, both options are unsatisfactory as (R)-2-methoxy-2-phonylacetic acid is extremely expensive and, regarding the latter case, virtually no resolution could be obtained with N-(para-toluenesulfonyl)-L-phenylalanine, in the hands of the inventors of the present invention. Likewise, the use of N-(para-toluenesulfonyl)-L-phenylalanine in the dielectrically controlled resolution of 3-aminopiperidine via the diastereomeric acid addition salt, as described by Sakurai et al., Tetrahedron Asymmetry 2012 23, 221-224, resulted in either poor yield or insufficient enantomeric excess.
WO 2007/075630 discloses the chiral resolution of 3-aminopiperidine via diastereomeric acid addition salts formed with dibenzoyl-L-tartaric acid, di(ortho-tolyl)-L-tartaric acid and N-acetyl-phenylalanine. However, all these chiral acids are instable and lead to only modest resolution at the most.
Therefore, there is still a strong need for providing a process for preparing APIP, that overcomes the disadvantages of the prior art. In addition, in case such a process, or another process for preparing APIP, yields racemic or insufficiently enantiomerically enriched APIP, there is also a need for a process enabling enantiomeric enrichment of APIP, in particular of (R)-APIP, which does not suffer the deficiencies of the prior art.